This project is designed to test the hypothesis that somatomedin (SM) secretion in fetal life is controlled by hormones other than growth hormone (GH). Growth is dependent upon GH in a young animal, but not in the fetus. At birth, animals decapitated in utero or children with congenital hypopituitarism do not exhibit growth retardation. Recent evidence suggests that SM is an important regulator of fetal growth and the liver is one of its major sources. Thus, I will study the effect of various hormones on the synthesis and release of SM by primary cultures of isolated hepatocytes from fetal, newborn and weanling rats. In my preliminary experiments placental lactogen stimulated a large increase in the SM concentration of the culture medium, but rat GH produced only small changes. The proposed experiments are divided into two phases: PHASE ONE: Ontogenesis of the hormonal regulation of SM secretion. To determine the hormonal requirements for SM secretion, hepatocytes from 20 day old fetuses will be placed in primary culture and incubated with various hormones. The SM content of the medium will be measured by a placental membrane radioreceptor assay, using 125I-MSA as the radioligand. The combination of hormones found to maximally stimulate SM secretion will be used to study the ontogenesis of SM secretion in hepatocytes from rats of various fetal and developmental ages. To determine if a relationship exists between the in vitro regulation and serum hormones, I will measure the circulating levels of the hormones affecting SM secretion in animals of the same ages. PHASE TWO: Mechanisms of hormonal regulation of SM secretion. I will attempt to determine what mechanisms mediate the age-related changes in the hormonal regulation of SM by investigating SM binding to proteins, hormone binding characteristics of the hepatocytes, the role of cyclic nucleotides and the relative importance of de novo synthesis versus release of preformed SM. These experiments should advance our understanding of fetal growth and could provide the basis for new modes of therapy for children with growth retardation.